{"doi":"10.1093/nar/gkab890","title":"Coupling high-throughput mapping with proteomics analysis delineates <i>cis</i>-regulatory elements at high resolution","abstract":"Growing evidence suggests that functional cis-regulatory elements (cis-REs) not only exist in epigenetically marked but also in unmarked sites of the human genome. While it is already difficult to identify cis-REs in the epigenetically marked sites, interrogating cis-REs residing within the unmarked sites is even more challenging. Here, we report adapting Reel-seq, an in vitro high-throughput (HTP) technique, to fine-map cis-REs at high resolution over a large region of the human genome in a systematic and continuous manner. Using Reel-seq, as a proof-of-principle, we identified 408 candidate cis-REs by mapping a 58 kb core region on the aging-related CDKN2A/B locus that harbors p16INK4a. By coupling Reel-seq with FREP-MS, a proteomics analysis technique, we characterized two cis-REs, one in an epigenetically marked site and the other in an epigenetically unmarked site. These elements are shown to regulate the p16INK4a expression over an ∼100 kb distance by recruiting the poly(A) binding protein PABPC1 and the transcription factor FOXC2. Downregulation of either PABPC1 or FOXC2 in human endothelial cells (ECs) can induce the p16INK4a-dependent cellular senescence. Thus, we confirmed the utility of Reel-seq and FREP-MS analyses for the systematic identification of cis-REs at high resolution over a large region of the human genome.","journal":"Nucleic Acids Research","year":2021,"id":202904,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392582,"name":"Danli Jiang","orcid":"0000-0002-9634-1736","position":1,"is_corresponding":false},{"id":530544,"name":"Meijuan Zou","orcid":"0000-0003-0056-2049","position":2,"is_corresponding":false},{"id":392586,"name":"Wei Sun","orcid":"0000-0002-5255-1213","position":3,"is_corresponding":false},{"id":37265,"name":"Di Wu","orcid":"0000-0001-8331-2357","position":4,"is_corresponding":false},{"id":27487,"name":"Jing Cui","orcid":"0000-0001-8657-1741","position":5,"is_corresponding":false},{"id":784150,"name":"Ian Huntress","orcid":null,"position":6,"is_corresponding":false},{"id":228260,"name":"Xinxia Peng","orcid":"0000-0002-0117-3582","position":7,"is_corresponding":false},{"id":392587,"name":"Gang Li","orcid":"0000-0003-1725-6611","position":8,"is_corresponding":false},{"id":392584,"name":"Ting Wu","orcid":"0000-0001-8152-1112","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:51:14.206397Z","pmid":"34634809","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}